In 1901, antibodies were described as magic bullets, and it was suggested that their specificity could be employed to direct therapies at a population of cells whose eradication was desirable. The decades since this vision have witnessed repeated attempts to generate antibodies directed against antigens that are absolutely specific for a defined population of cells, such as tumor cells. Monoclonal antibodies have been generated that react with tumor cells to a greater degree than with normal tissues, but none have been shown to be absolutely specific for tumor cells. With the possible exception of the antigens associated with B-cell lymphoma against which anti-idiotype antibodies are directed, no tumor-specific antigens suitable as targets for antibody-guided therapy have been discovered. Instead, antigens with quantitatively augmented expression on tumors and/or restricted and/or diminished expression on normal tissues have been used to develop antibodies for diagnostic and therapeutic uses. When normal cross-reactive tissues are not vital or replicable (e.g., normal T-cells), the problems associated with delivery of diagnostic or therapeutic agents to non-target cross-reactive tissues are less acute. However, the more potent the therapy, the more cross-reactivity may compromise safety and, therefore, the maximum tolerated dose that may be administered is lowered. Delivery of diagnostic agents to normal cross-reactive tissues may result in misdiagnosis.
A need remains for antibodies of improved specificity for target tissue such as tumors and decreased cross-reactivity with non-target (e.g., normal) tissues. This would be accomplished by identification of absolutely tumor-specific antigens and antibodies or by improved immunization techniques to yield totally tumor-specific antibodies. It is possible, however, that such target tumor-specific antigens do not exist, and that antibodies having the desired degree of specificity therefore will never be isolated.